Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity

• Elisabeth Rouits

  1Laboratoire d’Oncopharmacologie-INSERM U564, ANGERS Cedex 01, and

• Michèle Boisdron-Celle

  1Laboratoire d’Oncopharmacologie-INSERM U564, ANGERS Cedex 01, and

• Agnès Dumont

  1Laboratoire d’Oncopharmacologie-INSERM U564, ANGERS Cedex 01, and

• Olivier Guérin

  2Département d’Oncologie Médicale, Centre Régional de Lutte Contre le Cancer, Paul Papin-Angers, France

• Alain Morel

  1Laboratoire d’Oncopharmacologie-INSERM U564, ANGERS Cedex 01, and

• Erick Gamelin

  1Laboratoire d’Oncopharmacologie-INSERM U564, ANGERS Cedex 01, and

抄録

Purpose: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert’s syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients. Experimental Design: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment. Results: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert’s syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity. Conclusions: The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert’s syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity.

収録刊行物

• Clinical Cancer Research

  Clinical Cancer Research 10 (15), 5151-5159, 2004-08-01

  American Association for Cancer Research (AACR)

キーワード

• Cancer Research
• Oncology

詳細情報

• CRID: 1363670320770198272
• NII論文ID: 30018692206
• DOI: 10.1158/1078-0432.ccr-03-0548
• ISSN: 15573265
• ISSN: 10780432
• Web Site: https://aacrjournals.org/clincancerres/article-pdf/10/15/5151/1951759/zdf01504005151.pdf
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